Levobupivacaine: a new safer long acting local anaesthetic agent

The choice of local anaesthetic is influenced by several factors; it must provide effective anaesthesia and analgesia for the duration of the procedure and meet the expectations for post-operative pain management. Of primary concern is patient safety. Bupivacaine, currently the most widely used long acting local anaesthetic agent in both surgery and obstetrics, generally has a good safety record but its use has resulted in fatal cardiotoxicity, usually after accidental intravascular injection. Hence, for several years there has been a need for a long acting local anaesthetic, similar to bupivacaine, but with an improved cardiovascular safety profile. Levobupivacaine, the single enantiomer version of bupivacaine, offers a new long acting local anaesthetic, clinically equivalent in anaesthetic potency to bupivacaine, but with a reduced toxicity profile. Preclinical studies, from in vitro in single ion channels to whole large animal models, have unquestionably demonstrated that levobupivacaine is significantly less CNS toxic and cardiotoxic than bupivacaine. Cardiotoxicity is less easy to study in man, as the clinical signs are not usually seen until the CNS toxicity is marked, and well beyond that which is tolerable to volunteers or patients. Nevertheless, levobupivacaine has been shown to have less effect on myocardial contractility and QTc prolongation, early signs of cardiotoxicity, than bupivacaine in healthy subjects. In clinical use levobupivacaine has been shown to be equally efficacious as bupivacaine at comparable doses and concentrations, and has been found to produce similar anaesthetic characteristics (onset, duration and density of block). As levobupivacaine now becomes commercially available, the database available with which to make efficacy and safety comparisons with other local anaesthetics will increase, and the true value of this new long acting local anaesthetic should become even more apparent.     

Levobupivacaine: a review of its pharmacology and use as a local anaesthetic

Based on findings that the cardiotoxicity infrequently observed with racemic bupivacaine shows enantioselectivity, i.e. it is more pronounced with the R(+)-enantiomer, the S(-)-enantiomer (levobupivacaine) has been developed for clinical use as a long acting local anaesthetic. The majority of in vitro, in vivo and human pharmacodynamic studies of nerve block indicate that levobupivacaine has similar potency to bupivacaine. However, levobupivacaine had a lower risk of cardiovascular and CNS toxicity than bupivacaine in animal studies. In human volunteers, levobupivacaine had less of a negative inotropic effect and, at intravenous doses >75 mg, produced less prolongation of the QTc interval than bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with levobupivacaine. Levobupivacaine is long acting with a dose-dependent duration of anaesthesia. The onset of action is < or = 15 minutes with various anaesthetic techniques. In studies of surgical anaesthesia in adults, levobupivacaine provided sensory block for up to 9 hours after epidural administration of < or = 202.5 mg, 6.5 hours after intrathecal 15 mg, and 17 hours after brachial plexus block with 2 mg/kg. Randomised, double-blind clinical studies established that the anaesthetic and/or analgesic effects of levobupivacaine were largely similar to those of bupivacaine at the same dose. Sensory block tended to be longer with levobupivacaine than bupivacaine, amounting to a difference of 23 to 45 minutes with epidural administration and approximately 2 hours with peripheral nerve block. With epidural administration, levobupivacaine produced less prolonged motor block than sensory block. This differential was not seen with peripheral nerve block. Conditions satisfactory for surgery and good pain management were achieved by use of local infiltration or peribulbar administration of levobupivacaine. Levobupivacaine was generally as effective as bupivacaine for pain management during labour, and was effective for the management of postoperative pain, especially when combined with clonidine, morphine or fentanyl. The tolerability profiles of levobupivacaine and bupivacaine were very similar in clinical trials. No clinically significant ECG abnormalities or serious CNS events occurred with the doses used. The most common adverse event associated with levobupivacaine treatment was hypotension (31%). Conclusions: Levobupivacaine is a long acting local anaesthetic with a clinical profile closely resembling that of bupivacaine. However, current preclinical safety and toxicity data show an advantage for levobupivacaine over bupivacaine. Clinical data comparing levobupivacaine with ropivacaine are needed before the role of the drug can be fully established. Excluding pharmacoeconomic considerations, levobupivacaine is an appropriate choice for use in place of bupivacaine.     

Update on ropivacaine

Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new long-acting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t(1/2)), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.     

Cardiotoxicity with modern local anaesthetics: is there a safer choice?

The recognition that long-acting local anaesthetics, particularly bupivacaine the de facto standard long-acting local anaesthetic, were disproportionately more cardiotoxic than their shorter-acting counterparts stimulated the development of the bupivacaine congeners, ropivacaine and levobupivacaine. These agents, like all local anaesthetics, can produce cardiotoxic sequelae by direct and indirect mechanisms that derive from their mode of local anaesthetic actions, i.e. inhibition of voltage-gated ion channels. While all local anaesthetics can cause direct negative inotropic effects, ropivacaine and levobupivacaine are less cardiotoxic than bupivacaine judging by the larger doses tolerated in laboratory animal preparations before the onset of serious cardiotoxicity (particularly electro-mechanical dissociation or malignant ventricular arrhythmias). Additionally, they are less toxic to the CNS than bupivacaine judging by the larger doses tolerated before the onset of seizures. This may be clinically important because CNS effects may be involved in the production of serious cardiotoxicity. Preclinical studies in humans are a 'blunt instrument' in their ability to distinguish significant differences between these drugs because of the relatively small doses that can be used. Nevertheless, available evidence from human studies corroborates the preclinical laboratory animal studies. Because clinically significant differences between these drugs are more quantitative than qualitative, i.e. toleration of a larger dose before manifestation of toxicity, we have concluded that these newer agents have a lower risk of causing serious cardiotoxicity than bupivacaine. Thus, compared with bupivacaine, the newer agents may be seen as 'safer', but they must not be regarded as 'safe'.     

Update on ropivacaine

Long-acting local anaesthetics are primarily used in the practice of anaesthesia, particularly in regional anaesthesia and analgesia. Ropivacaine is a new longacting local anaesthetic that has been the focus of interest because of its increased cardiovascular safety compared with bupivacaine. Other advantages of ropivacaine over bupivacaine include a greater sensorimotor differential block and shorter elimination half-life (t_1/2), with a lower potential for accumulation. The most important attribute of ropivacaine, however, is its increased margin of safety compared with bupivacaine when given in equal doses. Many post-marketing studies have focused on the comparisons of efficacy in blocks and toxicity profiles of bupivacaine versus ropivacaine. Recent animal toxicity studies confirm the results of original studies showing that ropivacaine has less cardiovascular toxicity than bupivacaine with respect to direct myocardial depression, success of resuscitation and arrhythmogenic potential when given in equal doses. Reduced cardiotoxicity may be a distinct characteristic of ropivacaine. A review of current literature suggests that, at clinically relevant doses, ropivacaine provides the lowest potential risk of cardiotoxicity for inadvertent intravascular injection. Studies are currently under way comparing ropivacaine with levobupivacaine, the latest addition to the group of long-acting local anaesthetics.     

The local anaesthetic activity of levobupivacaine does not differ from racemic bupivacaine (Marcain): first clinical evidence

The local anaesthetic efficacy of levobupivacaine was compared with racemic bupivacaine (Marcain) in healthy male volunteers who were undergoing ulnar nerve blockade. Levobupivacaine, like racemic bupivacaine, produced blockade of nerve function with evidence of a dose response relationship for levobupivacaine. There were no statistically significant differences with respect to duration of sensory pain, sensory touch or motor block when the adjusted mean for the levobupivacaine groups (0.125, 0.25 and 0.5%) were compared with the 0.25% racemic bupivacaine control group. It is concluded that levobupivacaine is an effective local anaesthetic in humans with a dose-related duration of effect. Its local anaesthetic effect did not differ from that of racemic bupivacaine.     

Ropivacaine: a review of its use in regional anaesthesia and acute pain management

Ropivacaine (Naropin) is the pure S(-)-enantiomer of propivacaine, and is a long-acting amide local anaesthetic agent, eliciting nerve block via reversible inhibition of sodium ion influx in nerve fibres.Ropivacaine is a well tolerated regional anaesthetic effective for surgical anaesthesia as well as the relief of postoperative and labour pain. The efficacy of ropivacaine is similar to that of bupivacaine and levobupivacaine for peripheral nerve blocks and, although it may be slightly less potent than bupivacaine when administered epidurally or intrathecally, equi-effective doses have been established. Clinically adequate doses of ropivacaine appear to be associated with a lower incidence or grade of motor block than bupivacaine. Thus ropivacaine, with its efficacy, lower propensity for motor block and reduced potential for CNS toxicity and cardiotoxicity, appears to be an important option for regional anaesthesia and for the management of postoperative and labour pain.     

Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep

1. The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. 3. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (approximately 50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 micromol (approximately 2.5 mg) in 8 micromol increments, to either a fatal outcome or a 40 micromol (approximately 12.5 mg) maximum. 4. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean+/-s.e.mean actual fatal dose: 21.8+/-6.4 micromol), five of seven with levobupivacaine (22.9+/-3.5 micromol), four of six with ropivacaine (22.9+/-5.9 micromol). No significant differences in survival or in fatal doses between these drugs were found. 5. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.     

Comparison of intrathecal bupivacaine and levobupivacaine combined with opioids for Caesarean section

ABSTRACT

Objective: To date, racemic bupivacaine is the most popular local anaesthetic for spinal anaesthesia in parturients undergoing elective Caesarean delivery. However, data suggests that S-enantiomers like levobupivacaine may produce differential sensory and motor blockade. The aim of the present study was to compare fixed doses of intrathecal hypertonic levobupivacaine 0.5% (10?mg) and bupivacaine 0.5% (10?mg) combined with either intrathecal fentanyl (10 and 20?µg), or sufentanil (5?µg) in terms of sensory and motor block characteristics.

Research design and methods: 60 parturients with singleton pregnancy and > 34 weeks of gestation who underwent elective Caesarean delivery participated in this randomized, double-blinded clinical trial. They received spinal anaesthesia with either levobupivacaine or bupivacaine and the above mentioned opioids added (n = 10 parturients/group). Sensory block was assessed bilaterally by loss of cold sensation, and the degree of motor block was determined according to the Bromage scale every minute until delivery, subsequently at 5-min intervals until the end of surgery, and at 15-min intervals thereafter until complete resolution of spinal anaesthesia. A visual analogue scale was used postoperatively to measure duration of analgesia at 15-min intervals.

Main outcome measures: Levobupivacaine produced a significantly shorter and less pronounced motor blockade than racemic bupivacaine regardless of the kind and dose of opioid added. Duration of motor block Bromage 3 was 53 ± 14?min, 23 ± 18?min and 41 ± 8?min compared to 65 ± 25?min, 70 ± 19?min and 65 ± 22?min in the bupivacaine groups. Also, only n = 5/30 parturients reached Bromage3 in the levobupivacaine groups versus n = 21/30 parturients in the bupivacaine groups. No parturient experienced intraoperative pain. Adding sufentanil 5?µg to either local anaesthetic significantly prolonged duration of effective analgesia compared to supplemental fentanyl 10 or 20?µg.

Conclusions: Based on our data, 10?mg of hypertonic levobupivacaine 0.5% combined with sufentanil 5?µg was the most appropriate anaesthetic regimen in parturients undergoing elective Caesarean delivery in spinal anaesthesia.     

Benefit and risks of local anesthetics in infants and children

Regional anesthesia has become a routine part of the practice of anesthesiology in infants and children. Local anesthetic toxicity is extremely rare in infants and children; however, seizures, dysrhythmias, cardiovascular collapse, and transient neuropathic symptoms have been reported. Infants and children may be at increased risk from local anesthetics compared with adults. Larger volumes of local anesthetics are used for epidural anesthesia in infants and children than in adults. Metabolism and elimination of local anesthetics can be delayed in neonates, who also have decreased plasma concentrations of alpha(1)-acid glycoprotein, leading to increased concentrations of unbound bupivacaine. Most regional anesthetic procedures in infants and children are performed with the patient heavily sedated or anesthetized; because of this, and because a test dose is not a particularly sensitive marker of intravenous injection in the anesthetized patient, detection of intravascular local anesthetic injection is extremely difficult. The same local anesthetics used in adult anesthetic practice are also used in infants and children. Because of its extremely short duration of action, chloroprocaine has been used primarily for continuous epidural techniques in infants and children. The use of tetracaine has generally been limited to spinal and topical anesthesia. Lidocaine (lignocaine) has been used extensively in infants and children for topical, regional, plexus, epidural and spinal anesthesia. The association between prilocaine and methemoglobinemia has generally restricted prilocaine use in infants and children to the eutectic mixture of local anesthetics (EMLA). Because of its greater degree of motor block compared with other long-acting local anesthetics, etidocaine has generally been limited to plexus blocks in infants and children. Mepivacaine has been used for both plexus and epidural anesthesia in infants and children. Because postoperative analgesia is often the primary justification for regional anesthesia in infants and children, bupivacaine, a long-acting local anesthetic, is the most commonly reported local anesthetic for pediatric regional anesthesia. Given the lower toxic threshold of bupivacaine compared with other local anesthetics, the risk-benefit ratio of bupivacaine may be greater than that of other local anesthetics. Two new enantiomerically pure local anesthetics, ropivacaine and levobupivacaine, offer clinical profiles comparable to that of bupivacaine but without its lower toxic threshold. The extreme rarity of major toxicity from local anesthetics suggests that widespread replacement of bupivacaine with ropivacaine or levobupivacaine is probably not necessary. However, there are clinical situations, including prolonged local anesthetic infusions, use in neonates, impaired hepatic metabolic function, and anesthetic techniques requiring a large mass of local anesthetic, where replacement of bupivacaine with ropivacaine, levobupivacaine or (for continuous techniques) chloroprocaine appears prudent.     

左布比卡因的药动学特性、临床应用及其毒性

长效酰胺类局麻药布比卡因是左旋镜像体和右旋镜像体混合而成的消旋体，其毒性主要来自于右旋镜像体。左布比卡因保留了消旋布比卡因作用时间长、麻醉效能好的优点，且心脏和神经系统毒性小，目前用于临床麻醉及术后镇痛。现就其药动学、临床应用及对机体的毒性作一综述。     

Effects of levobupivacaine,ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block

1 Levobupivacaine and ropivacaine are the pure S(-) enantiomers of N-butyl- and N-propyl-2',6'-pipecoloxylidide, developed as less cardiotoxic alternatives to bupivacaine. In the present study, we have analysed the effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in CHO cells. 2 The three drugs blocked HERG channels in a concentration-, time- and state-dependent manner. Block measured at the end of 5 s pulses to -10 mV induced by 20 microM bupivacaine (52.7+/-2.0%, n=15) and ropivacaine (55.5+/-2.7%, n=13) was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5+/-4.2%, n=11) (P<0.05). 3 Dextrobupivacaine (20 microM) was less potent (47.2+/-5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG channel block. 4. Block induced by the three local anaesthetics exhibited a steep voltage dependence in the range of channel activation. In all cases, block measured at the maximum peak current at a test potential of 0 mV after promoting recovery from inactivation (I-->O) was lower than that observed at the end of 5-s pulses (I+O). 5. Levobupivacaine, ropivacaine and bupivacaine accelerated HERG inactivation kinetics, slowed the recovery from inactivation and shifted the inactivation curve towards more negative membrane potentials. The three local anaesthetics induced a rapid time-dependent decline after using a protocol that quickly activates HERG channels. 6. All these results suggest that: (1) these drugs bind to the open and the inactivated states of HERG channels, (2) they stabilize HERG channels in the inactivated state, and (3) block induced by bupivacaine enantiomers is stereoselective.     

Efficacy of levobupivacaine wound infiltration with and without intravenous lornoxicam for post-varicocoele analgesia: a randomized, double-blind study

BACKGROUND AND OBJECTIVE: The oxicam NSAID lornoxicam is a potent analgesic with excellent anti-inflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain. Levobupivacaine, the S-(-)-isomer of bupivacaine, is a long-acting local anaesthetic that can be infiltrated into wounds for management of postoperative pain. We assessed the analgesic efficacy of lornoxicam when administered as an adjuvant to levobupivacaine wound infiltration after varicocoele operation. METHODS: Sixty patients who underwent varicocoele surgery were randomly assigned to three different treatment groups. Before skin closure, patients received the following treatments: group I (n=20) patients received normal saline 20 mL wound infiltration and intravenous lornoxicam (Xefo, Nycomed Pharma AS, Roskilde, Denmark) 2 mL (8 mg); group II (n=20) patients received 0.25% levobupivacaine (Chirocaine, Abbott Scandinavia AB, Solna, Sweden) 10mL with normal saline 10 mL wound infiltration and intravenous normal saline 2 mL; group III (n=20) patients received 0.25% levobupivacaine 10 mL with normal saline 10 mL wound infiltration and intravenous lornoxicam 2 mL (8 mg). Pain scores and total pethidine (meperidine) consumption were measured at 1, 2, 4, 6, 12 and 24 hours postoperatively. Time to first analgesic requirement and patient satisfaction were also compared post-surgery. RESULTS: Pain scores during the first 6 hours postoperatively were significantly lower in group III than in group I and group II (p<0.01). Total pethidine consumption was significantly lower in group III (34.0+/-28.0 mg) than in group I (74.0+/-25 mg) and group II (76.0+/-29 mg) [p<0.01]. Time to first analgesic was also significantly longer in group III (14.8+/-8.4 hours) than in group I (6.2+/-5.2 hours) and group II (5.8+/-7.1 hours) [p<0.01]. The incidence of postoperative nausea and vomiting was significantly lower in group III than in group I and group II (p<0.05). More patients in group III described their analgesia as good or excellent than in group I or group II (p<0.01). CONCLUSION: In this study, levobupivacaine wound infiltration with adjuvant intravenous lornoxicam administration was associated with better postoperative analgesia during the early postoperative hours after varicocoele surgery than that induced by lornoxicam alone or levobupivacaine wound infiltration alone.     

Clinical application of ropivacaine for the lower extremity

Ropivacaine is a new amide local anaesthetic, which is the first commercially available in its category as a pure S-(-) enantiomer. In most recent studies, ropivacaine exhibited a very close pharmacodynamic profile to equipotent doses of bupivacaine. Concentrations of 0.5%, 0.75% and 1% (5, 7.5 and 10 mg/mL, respectively) ropivacaine are used for intraoperative anaesthesia, while the concentration of 0.2% (2 mg/mL) is preferred for postoperative analgesia, either alone or in combination with opioids and/or clonidine. Ropivacaine is responsible for excellent postoperative analgesia following epidural and peripheral perineural injections, using single-shot injections and continuous infusions. Differential sensory/motor block is only apparent at low concentrations (0.2% and less). A significant amount of recent literature focuses on its use for peripheral blocks of the lower limbs, i.e. sciatic and femoral nerve blocks. The primary benefit of ropivacaine is its lower toxicity, mainly lower cardiotoxicity, following accidental intravascular injection. This higher therapeutic index leads to an improved safety profile as compared with potent local anaesthetics such as racemic bupivacaine. For that reason, ropivacaine is a good choice for both intraoperative and postoperative regional anaesthesia and analgesia.     

Ropivacaine

Ropivacaine (Naropin, AstraZeneca) is a long-acting amide local anaesthetic released for clinical use in 1996. Similar to bupivacaine, ropivacaine is equally effective for s.c. infiltration, epidural and peripheral nerve block for surgery, obstetric and post-operative analgesia. Ropivacaine differs from most other amide-type local anaesthetics in that it is marketed as a pure S-enantiomer, instead of as a racemate. This feature improves the safety of ropivacaine, and, indeed, studies have shown ropivacaine to have less cardiovascular and CNS toxicity than bupivacaine. Ropivacaine is nearly identical to bupivacaine in onset, quality and duration of sensory block, but it produces less motor block. Whether or not the motor sparing effect of ropivacaine is due to a lower relative potency compared to bupivacaine is a matter of intense debate. Despite a better safety profile, the increased cost of ropivacaine may limit its clinical utility.     

左布比卡因硬膜外麻醉对腹部手术病人心肌酶的影响

目的:观察局部麻醉药(局麻药)左布比卡 因硬膜外麻醉对手术病人心肌酶谱的影响,并与布 比卡因作对比,评估其临床应用的安全性。方法:择 期行胆囊切除手术的病人60例,均行硬膜外麻醉, 随机双盲分成2组,左布比卡因组30例、布比卡因 组30例,2组分别用0.56%左布比卡因,或用0.56 %布比卡因,总量均为13mL;注射局麻药前及术后 24h取静脉血测定肝、肾功能及心肌酶谱。结果:2 组术后ALT,AST,BUN,Cr,LDH,α 羟丁酸脱氢酶 (BDH),肌酸激酶(CK)均有增高;与术前比较有显 著差异(P<0.05或P<0.01),组间比较除CK, BDH外均无显著差异(P>0.05),左布比卡因组和布比卡因组CK的增加值分别为(440±s120)U·L-1和(530±135)U·L-1,2组比较差异有非常显著意义(P<0.01)。2组麻醉疗效比较,差异无显著意义。结论:左布比卡因和布比卡因行硬膜外麻醉效果均较好,但以心肌酶的部分指标作比较左布比卡因更安全。     

Ropivacaine: an update of its use in regional anaesthesia

Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anaesthetic with a high pKa and low lipid solubility which blocks nerve fibres involved in pain transmission (Adelta and C fibres) to a greater degree than those controlling motor function (Abeta fibres). The drug was less cardiotoxic than equal concentrations of racemic bupivacaine but more so than lidocaine (lignocaine) in vitro and had a significantly higher threshold for CNS toxicity than racemic bupivacaine in healthy volunteers (mean maximum tolerated unbound arterial plasma concentrations were 0.56 and 0.3 mg/L, respectively). Extensive clinical data have shown that epidural ropivacaine 0.2% is effective for the initiation and maintenance of labour analgesia, and provides pain relief after abdominal or orthopaedic surgery especially when given in conjunction with opioids (coadministration with opioids may also allow for lower concentrations of ropivacaine to be used). The drug had efficacy generally similar to that of the same dose of bupivacaine with regard to pain relief but caused less motor blockade at low concentrations. Lumbar epidural administration of 20 to 30ml ropivacaine 0.5% provided anaesthesia of a similar quality to that achieved with bupivacaine 0.5% in women undergoing caesarean section, but the duration of motor blockade was shorter with ropivacaine. For lumbar epidural anaesthesia for lower limb or genitourinary surgery, comparative data suggest that higher concentrations of ropivacaine (0.75 or 1.0%) may be needed to provide the same sensory and motor blockade as bupivacaine 0.5 and 0.75%. In patients about to undergo upper limb surgery, 30 to 40ml ropivacaine 0.5% produced brachial plexus anaesthesia broadly similar to that achieved with equivalent volumes of bupivacaine 0.5%, although the time to onset of sensory block tended to be faster and the duration of motor block shorter with ropivacaine. Ropivacaine had an adverse event profile similar to that of bupivacaine in clinical trials. Several cases of CNS toxicity have been reported after inadvertent intravascular administration of ropivacaine, but only 1 case of cardiovascular toxicity has been reported to date. The outcome of these inadvertent intravascular administrations was favourable. CONCLUSION: Ropivacaine is a well tolerated regional anaesthetic with an efficacy broadly similar to that of bupivacaine. However, it may be a preferred option because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block.     

Protein kinases participate in the contraction in response to levobupivacaine in the rat aorta

Levobupivacaine is a long-acting amide local anesthetic that intrinsically produces vasoconstriction both in vivo and in vitro. Levobupivacaine increases intracellular calcium concentrations ([Ca(2+)](i)) in vascular smooth muscle cells. The goals of this in vitro study were to investigate whether levobupivacaine-induced contraction is associated with increased Ca(2+) sensitivity and to identify the protein kinases involved in mediating contraction in response to levobupivacaine in isolated rat aortic smooth muscle. The effect of levobupivacaine and potassium chloride (KCl) on the [Ca(2+)](i) and tension was measured simultaneously with acetoxymethyl ester of fura-2-loaded aortic strips. Cumulative levobupivacaine concentration-response curves were generated in the presence or absence of the following antagonists: GF 109203X; Y-27632; genistein; SP600125; PD 98059; and SB 203580. Levobupivacaine-induced protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and c-Jun NH(2)-terminal kinase (JNK) phosphorylation and Rho-kinase (ROCK-2) membrane translocation were detected in rat aortic vascular smooth muscle cells using Western blotting. The slope of the [Ca(2+)](i)-tension curve for levobupivacaine was higher than that for KCl. Y-27632, GF 109203X, and SP600125 attenuated levobupivacaine-induced contraction in a concentration-dependent manner. Genistein, PD 98059, and SB 203580 attenuated levobupivacaine-induced contraction. Pretreatment with GF 109203X and Y-27632 inhibited levobupivacaine-induced PKC phosphorylation and Rho-kinase (ROCK-2) membrane translocation, respectively. Pretreatment with SP600125 or PD 98059 attenuated the levobupivacaine-induced phosphorylation of JNK and ERK, respectively. These results indicate that levobupivacaine-induced contraction involving an increase in myofilament Ca(2+) sensitivity involves the primary activation of Rho-kinase-, PKC-, and JNK-mediated pathways of rat aortic smooth muscle.     

Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects.

1. The possibility of a pharmacokinetic interaction between the H2-receptor antagonist cimetidine and the long-acting local anaesthetic agent bupivacaine was studied in seven healthy, non-smoking volunteers. 2. The study consisted of two sessions at a minimum interval of 4 days. In a randomized, crossover fashion, the volunteers received bupivacaine HCl 1.4 mg kg-1 by i.m. injection at two occasions, once after no premedication, and once after two oral doses of 400 mg cimetidine. The concentrations of bupivacaine and its metabolites, 4'-hydroxybupivacaine and desbutylbupivacaine, were assayed by h.p.l.c., in serum up to 8 h and in urine fractions up to 24 h. 3. No influence of cimetidine on the pharmacokinetics of bupivacaine or on the serum cumulation of urinary recovery of its measured metabolites was detected. 4. These data suggest that cimetidine may be used safely as a premedication before local anaesthetic procedures with bupivacaine.